Hemoglobin is the most abundant reservoir of iron in the body. Pathogenic microorganisms have developed surface-exposed, Hb-binding receptors that enable the assimilation of Hb-iron. The PI and others have shown that the possession of Hb-binding receptors represents a virulence trait for bacteria. These receptors have, however, only recently become the object of investigation, and our understanding of Hb-iron is therefore very limited at present. In this respect, N. meningitidis, the most common causative agent of meningitis in children in the US, expresses different Hb-iron acquisition systems. The PI has recently identified and partially characterized the Hb-binding outer membrane receptor (HmbR) of Neisseria meningitidis HmbR was expressed in all tested N. meningitidis strains. HmbR is likely a virulence factor because an hmbR mutant was impaired in virulence in an infant rat model. The mechanism and protein domains by which HmbR (or any other Hb bacterial receptor) binds and uses Hb as a source of iron are unknown. To fully understand the role of Hb-iron acquisition in virulence, the PI proposes to identify and characterize all meningococcal systems involved in Hb utilization. The PI and others have identified a second and third Hb- acquisition system of meningococci. The PI will genetically characterize the third system and use well-defined mutants in all three systems to assess the role of Hb-iron acquisition in virulence of meningococci. The study of Hb-iron acquisition systems will not only contribute to our understanding of meningococcal virulence, but could also identify new vaccine targets against N. meningitidis. Finally, understanding Hb-iron acquisition systems may assist scientists in design of a new family of Hb-based blood substitutes that do not increase the risk of infection by Hb-utilizing bacteria.